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INTRODUCTION — Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. It most frequently affects infants from birth to 18 months of age, but the disease is also observed in children and adults of all ages. HLH can occur as a familial or sporadic disorder, and it can be triggered by a variety of events that disrupt immune homeostasis. Infection is a common trigger both in those with a genetic predisposition and in sporadic cases.

Prompt initiation of treatment is essential for the survival of affected patients. Often the greatest barrier to a successful outcome is a delay in diagnosis, which is difficult because of the rarity of this syndrome, the variable clinical presentation, and the lack of specificity of the clinical and laboratory findings.

TERMINOLOGY — Terms used to describe HLH and related syndromes have evolved since the original patient was described as having "familial hemophagocytic reticulosis" in 1952.

Use of the term "primary HLH" to denote the presence of an underlying genetic disorder and "secondary HLH" to denote presence of the HLH phenomenon occurring secondary to another condition has caused a great deal of confusion among clinicians. Both primary and secondary HLH can be triggered by infections or other immunologically activating events, and gene mutations can be found in individuals of any age and with any family history. In practice, distinction between primary and secondary HLH is not essential for the initial diagnosis and management. However, identification of a gene mutation may be useful for subsequent management. (See 'Evaluation and diagnostic testing' below.)

●Secondary (sporadic, acquired) HLH has generally been used to describe those without a known familial mutation; adults; and those for whom a clear trigger of the HLH episode has been identified (eg, viral illness, autoimmune disease, lymphoma). However, this term can create confusion because many patients with "secondary HLH" do in fact have a genetic defect associated with the syndrome (eg, heterozygous defect, mutation resulting in partial protein expression), and many patients with primary HLH experience symptoms in response to one of these triggers. (See 'Triggers' below.)

Immunologic abnormalities — HLH is not a malignancy; it is a syndrome of excessive inflammation and tissue destruction due to abnormal immune activation and excessive inflammation. In general, the excessive inflammation is thought to be caused by a lack of normal downregulation of activated macrophages and lymphocytes [7].

The cell types involved in the pathogenesis of HLH include the following:

Consistent with this mechanism, most patients with HLH exhibit impaired cytotoxic function of NK cells and CTLs, coupled with excessive activation of macrophages [9-14]. Excessive cytokine production by macrophages, NK cells, and CTLs is thought to be a primary mediator of tissue damage [7]. (See 'Immunologic profile' below and 'Cytokine storm' below.)

Toll-like receptor (TLR) activation of the immune system can be another cause of HLH [15]. TLRs are non-antigen-specific receptors on the surface of NK cells that are activated by components of bacteria, fungi, viruses, or mycoplasma. Normal mice with repeated TLR9 stimulation develop an illness similar to MAS [16]. Genes associated with TLR/interleukin 1 receptor (IL-1R) signaling are upregulated in patients with juvenile idiopathic arthritis and MAS [17].

Hemophagocytosis — In addition to antigen presentation and cytokine production, macrophages can also phagocytize host cells. Hemophagocytosis refers to the engulfment (literally "eating") of host blood cells by macrophages. Hemophagocytosis is characterized by the presence of red blood cells, platelets, or white blood cells (or fragments of these cells) within the cytoplasm of macrophages (picture 1 and picture 2). It can be seen on biopsies of immune tissues (lymph nodes, spleen, liver) or bone marrow aspirates/biopsies. Although it can be a marker of excessive macrophage activation and supports the diagnosis of HLH, hemophagocytosis alone is neither pathognomonic of, nor required for, an HLH diagnosis. (See 'Bone marrow evaluation' below and 'Diagnosis' below.)

Cytokine storm — The persistent activation of macrophages and NK cells and CTLs that occurs in patients with HLH leads to excessive cytokine production (cytokine storm) by all of these cells. It is thought that the excessive cytokines are ultimately responsible for multiorgan failure and the high mortality of the syndrome [7,18,19].

Cytokines found at extremely high levels in the plasma of patients with HLH include interferon gamma (Ifn-γ); tumor necrosis factor alpha (TNF-α); interleukins (IL) such as IL-6, IL-10, and IL-12; and the soluble IL-2 receptor (CD25) [20-22]. Elevated IL-16 levels may be important for a TH1-type response that recruits macrophages and other cells implicated in HLH [23]. In a study of adults with secondary HLH, markedly elevated levels of IL-18 and its binding protein were found [24]. Some of these cytokines can be measured in serum and are useful in distinguishing HLH from other conditions. A study of IFN-γ, IL-6, and IL-18 in patients with systemic JIA (sJIA) versus HLH showed higher levels of IFN-γ and IFN-γ-induced proteins in HLH compared with sJIA, but the ratio of IL-18/IFN-γ was higher in sJIA [25]. (See 'Specialized testing' below.)

Triggers — Patients with HLH can have a single episode of the disease or relapsing episodes. The initiating trigger for an acute episode is often an infection or an alteration in immune homeostasis. The two broad categories of triggers include those that cause immune activation, and those that lead to immune deficiency.

Immune activation is typically initiated by an infection. Infection is a common trigger both in those with a genetic predisposition and in sporadic cases. The most common infectious trigger for HLH is viral infection, especially with Epstein-Barr virus (EBV) [7]. Primary EBV infection can trigger HLH in individuals with a defect in perforin-dependent cytotoxicity as well as those without a known predisposition; patients with X-linked lymphoproliferative disease (XLP) are at particularly high risk [26]. Kawasaki disease, a common vasculitis of childhood, can also trigger HLH. Many other infectious organisms are also implicated. (See 'Immunodeficiency syndromes' below and 'Infections' below and "Kawasaki disease: Clinical features and diagnosis".)

The excessive cytokine release in patients with chronic granulomatous disease (CGD) may also lead to HLH, as 3 of 17 patients with CGD at one institution developed HLH [27]. The HLH in these patients was controlled with antimicrobials, steroids, and intravenous immune globulin (IVIG).

The coexistence of immune dysregulation with unchecked inflammation distinguishes HLH from other syndromes of immune activation, immunodeficiencies, and inflammatory states [26].

GENETICS — Genetic defects play a major role in childhood HLH and are increasingly found in adult cases [14,28-32]. Most of the implicated genes encode components of the machinery for perforin-dependent cytotoxicity (figure 1) [33]. (See 'Pathophysiology' above.)

These genes act in an autosomal recessive fashion (ie, inheritance of a mutation at both alleles of a gene is required to manifest the disease); however, heterozygosity for an HLH mutation is occasionally found in an individual (typically an adult) with HLH associated with another condition [34]. (See 'Associated illnesses' below.)

In addition to homozygous mutation in a single HLH gene, individuals with HLH may be compound heterozygotes (ie, they may have a different mutation in each allele of the same gene) or they may show digenic inheritance (ie, they may have separate mutations in two different genes). A review of 2701 patients referred for genetic testing revealed that 225 (8 percent) were homozygous or compound heterozygous for mutations, and 28 (1 percent) showed digenic inheritance [32]. Another study reported similar findings, with monoallelic mutations of known familial HLH genes found in 43 of 281 patients classified as having "sporadic" disease, suggesting that this disorder is not a simple recessive one [35].

In a study that used whole exome sequencing, heterozygous variants in LYST, MUNC13-4, and STXBP2 were discovered in 5 of 14 patients with juvenile idiopathic arthritis (JIA) who had macrophage activation syndrome (MAS), but in only 4 of 29 patients with JIA who did not have MAS [36]. Several other recessive pairs and compound heterozygotes were found.

The presence of homozygous, compound heterozygous, or digenic mutations in a patient with suspected HLH (or a heterozygous mutation in an adult) is sufficient for diagnosis. Genetic information can also be helpful in determining the likelihood of recurrence, the need for hematopoietic cell transplant, and the risk of HLH in family members. (See 'Diagnosis' below and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

The likelihood of identifying a gene mutation is highest in the youngest patients. In a review of 476 North American children, a gene mutation was identified in 45 percent of those less than one month of age [26]. In those aged between two months to one year, one to two years, and greater than two years, the frequencies of identifying a gene mutation were 39, 20, and 6 percent, respectively.

In another study of 175 adults (age range, 18 to 75 years), 14 percent had gene mutations; these tended to cause partial defects in protein function rather than complete loss of the protein [37]. This partial loss of function may explain the later age of HLH onset in some adults. (See 'Features in adults' below.)

●PRF1/Perforin – FHL2 results from mutations in the PRF1 gene, which encodes perforin. Perforin is delivered in cytolytic granules and forms pores in the membrane of target cells. Mutations in other genes that affect perforin expression have also been reported [29,38-40].

●STX11/Syntaxin 11 – FHL4 results from mutations in the STX11 gene, which encodes Syntaxin 11. Syntaxins control granule exocytosis. Several Syntaxin mutations were reported in a group of Kurdish families with HLH [31,42].

●STXBP2/Munc18-2 – FHL5 results from mutations in the STXBP2 gene, which encodes Munc18-2 (also called Syntaxin binding protein 2) [34,43]. This protein binds to Syntaxin 11 and promotes the release of cytotoxic granules.

The gene defect responsible for FLH1 remains uncharacterized.

Immunodeficiency syndromes — Several mutations that cause congenital immunodeficiency syndromes are also associated with an increased incidence of HLH. These include the following:

●Interleukin-2-inducible T cell kinase (ITK) deficiency – These patients, like those with XLP and XMEN deficiencies, are unable to control EBV infections. They have a variety of lymphoproliferative diseases, lymphomatoid granulomatosis, HLH, and dysgammaglobulinemia.

Genotype-phenotype correlations — Patients with HLH gene mutations tend to present at a younger age than those without mutations. In addition, the specific gene mutated and the mutation site may affect the age of presentation. These observations are supported by the following reports:

●Patients with PRF1 null mutations typically present within the first year of life, whereas those with missense mutations and variable degrees of perforin expression have a more variable age of presentation, even into adulthood [5,52-58].

●In a series of 76 patients with HLH, those with PRF1 mutations had a significantly higher risk of early disease onset (ie, <6 months) than those with STX11 mutations (adjusted odds ratio 8.2; 95% CI 1.2-56) [59].

●In another study, the most common PRF1 mutation in African blacks (50delT-PRF1) was found to be associated with an earlier age of disease onset compared with that reported for other PRF1 mutations (median age at diagnosis, three months for 50delT-PRF1 verus 36 months for others) [54,60].

●In a series of patients with digenic inheritance (inheritance of mutations at two separate FLH loci), PRF1 mutation in combination with a mutation affecting degranulation (eg, UNC13D, STX11, STXBP2) predicted disease onset at age two years or greater, whereas two mutations affecting degranulation predicted disease onset at <2 years of age [32].

●Adult patients with hypomorphic mutations of PRF1, MUNC13-4, and STXBP2 often have a more indolent course than younger patients [37].

EPIDEMIOLOGY — HLH is primarily a pediatric syndrome. Infants are most commonly affected, with the highest incidence in those <3 months [62]. The male-to-female ratio is close to 1:1 [62]. In adults, there may be a slight male predisposition [63].

Based on the incidence at several tertiary care pediatric hospitals, we estimate that approximately 1 child in 3000 admitted to the hospital will have HLH, translating to several cases per year [26]. Earlier reviews of the epidemiology of HLH reported incidences that were much lower, likely reflecting underdiagnosis of the condition. As an example, in a series from the 1970s that reported an incidence of 1.2 children per million per year, the diagnosis of HLH was made antemortem in only 11 of 32 patients [62]. A review of HLH cases from the largest pediatric hospitals in Texas revealed an incidence of 1 in 100,000 children [64].

Although HLH is primarily a pediatric disease, it is diagnosed in patients of all ages, including adults as old as 70 years of age [5,52,65]. A review of 2197 adult cases worldwide found that approximately half of reported patients were from Japan [63]. A nationwide survey in Japan from 2001 to 2005 identified 799 patients with HLH; of the 470 with sufficient data for analysis, 192 (41 percent) were older than 14 years [66]. In addition, there seems to be an ethnic predisposition for development of malignancy-associated HLH, with one large study demonstrating a much higher risk in Japanese and East Asian patients with malignancy compared with Western patients [67].

Up to 25 percent of HLH cases are familial. As previously noted, the transmission of HLH is autosomal recessive, and parental consanguinity is common. (See 'Genetics' above.)

The frequency of specific HLH mutations was evaluated in a multi-ethnic cohort of 76 patients with familial HLH originating from 65 unrelated families [59]. In this cohort, mutations in STX11, PRF1, and UNC13D were found in 20, 18, and 10 percent of affected individuals, respectively.

A review of 224 North American patients with HLH mutations found the following distribution of specific mutations according to ethnicity [26]:

●Whites were most likely to have mutations in UNC13D (47 percent), STXBP2 (22 percent), and PRF1 (20 percent)

●Hispanics were most likely to have mutations in PRF1 (71 percent) and UNC13D (17 percent)

●Blacks were most likely to have mutations in PRF1 (98 percent)

●Arabs were most likely to have mutations in PRF1 (36 percent), UNC13D (27 percent), and STXBP2 (18 percent)

Other studies of specific ethnic groups have found the following distributions:

●Individuals of Turkish origin had a high incidence of mutations in PRF1, UNC13D, or STX11 [68].

●Individuals from Saudi Arabia, the United Arab Emirates, and Turkey had a high incidence of STXBP2 mutations [53,69,70].

Initial presentation — HLH presents as a febrile illness associated with multiple organ involvement. Thus, initial signs and symptoms of HLH can mimic common infections, fever of unknown origin, hepatitis, or encephalitis. With few exceptions, the clinical features are similar regardless of whether an underlying genetic defect has been identified. (See 'Genotype-phenotype correlations' above.)

In the HLH-94 study of 249 patients, which is one of the largest cohorts described, prominent clinical signs included the following [72]:

●Hepatomegaly – 95 percent

●Lymphadenopathy – 33 percent

●Neurologic symptoms – 33 percent

●Rash – 31 percent

In a European registry that included 122 patients, splenomegaly was seen in 97 percent, and fever in 93 percent [3].

Some HLH gene mutations are associated with distinct clinical features in addition to the typical presenting signs and symptoms. As an example, a review of 37 patients with STXBP2 mutations reported hypogammaglobulinemia, severe diarrhea, bleeding, and sensorineural hearing loss in 59, 38, 22, and 16 percent, respectively [53]. Defective granule mobilization of neutrophils has also been identified in these patients [73]. This leads to inadequate bacterial killing, especially of gram negative bacteria, and is hypothesized to lead to the association of chronic diarrhea in this subset of HLH patients.

Some clinical findings are observed less frequently in affected patients from different ethnic groups. This was illustrated in a case series of 20 neonates from Japan, in which the incidence of fever was extremely low in the eight preterm infants (12 percent); hypertriglyceridemia and neutropenia were uncommon; and familial mutations were undetectable in most patients (65 percent) [74].

Laboratory and radiographic abnormalities

Cytopenias — Cytopenias, especially anemia and thrombocytopenia, are seen in greater than 80 percent of patients on presentation [64,72,75]. Platelet counts range from 3000 to 292,000 (median 69,000)/microL, and hemoglobin levels of 3.0 to 13.6 (median 7.2) g/dL are typical [64].

Cytopenias may occur later in the disease course in those with macrophage activation syndrome (MAS; ie, HLH in the setting of a rheumatologic disorder), especially those with juvenile idiopathic arthritis (JIA), because patients with JIA often have elevated blood counts prior to developing MAS.

Serum ferritin levels — A very high serum ferritin level is common in HLH. In the HLH-94 study, ferritin levels greater than 500, 5000, and 10,000 ng/mL were seen in 93, 42, and 25 percent, respectively; the median ferritin level was 2950 ng/mL [72]. Serum ferritin in this range is seen in very few other inflammatory disorders in children, and when it does occur in other syndromes, it is often in the setting of iron overload syndromes (eg, in multiply transfused patients). This was illustrated in a series of 330 children with high serum ferritin levels (320 controls and 10 HLH patients), in which a ferritin level >10,000 mcg/L was 90 percent sensitive and 96 percent specific for HLH, with very minimal overlap with sepsis, infections, and liver failure [76]. When the control group was re-analyzed with a comparison cohort of 120 patients with HLH, a ferritin level ≥2000 mcg/L had a 70 percent sensitivity and 68 percent specificity for diagnosing HLH [77]. There was no difference when primary and secondary HLH cases were analyzed separately.

While a very high ferritin level is helpful in suggesting the possibility of HLH, a low ferritin (eg, ferritin <500 ng/mL) does not exclude the possibility of HLH. A relatively normal ferritin can occasionally be seen in HLH genetic syndromes, even during a disease flare, and disease activity in some patients may correlate more closely with elevated soluble IL-2 receptor alpha (sIL-2R or sCD25) than with ferritin.

Interestingly, macrophages are a primary source of ferritin, which may explain the association between HLH and very high ferritin levels [78]. A protein responsible for modulation of iron homeostasis, growth differentiation factor 15, is dramatically upregulated in patients with HLH and is responsible for increased serum ferritin by enhancing the ferroportin-mediated iron efflux [79].

●Liver enzyme levels greater than three times the upper limit have been reported in 50 to 90 percent of patients with HLH [64,75,80]; LDH is elevated in 85 percent [75]. Bilirubin levels between 3 and 25 mg/dL are seen in greater than 80 percent. The GGT level is an especially sensitive number to follow because of biliary tract infiltration by lymphocytes and macrophages [26].

●Hypertriglyceridemia may be due to severe liver involvement, and triglycerides may not be elevated until the liver has been affected for some time. In a review of patients with HLH associated with a variety of triggers, 68 percent had elevated triglycerides at diagnosis or during the course of the disease [81].

●Liver biopsy, if done, is likely to show lymphocytic infiltrates in patients with HLH. On autopsy, the livers of patients who have died from HLH show chronic persistent hepatitis with periportal lymphocytic infiltration [83].

Neurologic findings — Neurologic abnormalities have been observed in one-third of patients with HLH. The types of abnormalities may be highly variable, and include seizures, mental status changes (including severe changes consistent with encephalitis), and ataxia [7,26,84]. Sometimes these findings dominate the clinical picture or develop prior to the appearance of other signs and symptoms [85,86]. As examples, two patients with familial HLH due to a mutation in the PRF1 gene presented with only severe encephalitis, while another child presented with a demyelinating peripheral neuropathy caused by diffuse macrophage infiltration of the nerve sheath [87,88].

Magnetic resonance imaging (MRI) of the brain in patients with HLH also may show hypodense or necrotic areas [89]. Approximately 50 percent of patients have abnormalities of the cerebrospinal fluid, which may carry an increased risk for mortality and neurologic sequelae [90]. In a series of 10 adults with HLH, seven had neurological impairment, which included encephalopathy and seizures. Basal ganglia abnormalities were found in four patients [91]. (See 'Initial evaluation' below and "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'Prognosis'.)

Other findings — HLH can affect other organ systems, including the respiratory system, heart, and skin.

●Respiratory abnormalities may lead to an urgent need for ventilatory support and death from acute respiratory distress syndrome. Deteriorating respiratory function may be due to worsening of the HLH (causing an acute respiratory distress syndrome [ARDS]-like syndrome), or due to an infection. Pulmonary involvement was reported in 42 percent of a series of 775 adults with HLH [63].

●Severe hypotension may require administration of one or more vasopressors.

●Renal dysfunction occurs in many patients and may present with hyponatremia, perhaps caused by a SIADH mechanism. Many patients develop renal failure and require dialysis. Renal involvement was reported in 16 percent of a series of 775 adults with HLH [63].

●Skin manifestations can be quite varied. These include generalized rashes, erythroderma, edema, petechiae, and purpura. Skin rash was reported in one-quarter of a series of 775 adults with HLH [63].

●Bleeding is also a common manifestation of HLH. It may be due to altered coagulation from liver failure, thrombocytopenia from bone marrow failure, or platelet function defects associated with an underlying genetic defect in platelet granule processing. (See 'Genetics' above.)

It is important to identify these conditions because effective treatment may lead to clinical improvement of the HLH and allow the patient to avoid more toxic therapy (eg, hematopoietic cell transplant). However, evaluation for these associated syndromes should not delay diagnostic testing or initiation of HLH-specific treatment in those who are acutely ill.

Infections — HLH is often associated with infections, especially viral. Common viruses include Epstein-Barr virus, cytomegalovirus, parvovirus, herpes simplex virus, varicella-zoster virus, measles virus, human herpes virus-8, H1N1 influenza virus, parechovirus, and HIV, alone or in combination [63,92-100]. The development of HLH shortly after the initiation of antiretroviral therapy (ART) for the treatment of HIV infection has also been reported [101]. Patients with rheumatologic diseases who are treated with anti-TNF agents and develop HLH may be infected with mycobacterium tuberculosis, cytomegalovirus, EBV, Histoplasma capsulatum, and other bacteria [102].

Although less common, HLH may also occur in the setting of infections due to bacteria (eg, Brucella, gram negative bacteria, tuberculosis), parasites (eg, Leishmaniasis, malaria), and fungi [63,100,103,104].

Malignancy — HLH has been reported in association with malignancies, most commonly lymphoid cancers, including T, NK, and anaplastic large cell lymphomas, and leukemias [100,105-114]. B cell lymphoblastic leukemia, myeloid malignancies, and solid tumors occurring in association with HLH have also been noted [26,107,115-117]. Rarely, the diagnosis of HLH may precede the identification of the malignancy [118].

HLH may develop any time during the course of a rheumatologic disorder (eg, upon presentation, during therapy, in association with a concurrent infection). In patients with sJIA treated with tocilizumab, 23 of 394 developed confirmed or probable MAS [120]. When MAS occurs as a presenting manifestation of lupus and systemic juvenile or adult rheumatoid arthritis, the diagnosis of both conditions may be challenging. Other autoimmune diseases associated with HLH include dermatomyositis, systemic sclerosis, mixed connective tissue disease, antiphospholipid syndrome, Sjögren's syndrome, ankylosing spondylitis, vasculitis, and sarcoidosis [82]. Some patients with MAS have also been found to have heterozygosity for mutations in HLH genes (eg, PRF1, UNC13D) [36]. (See 'Genetics' above.)

Immunodeficiency — HLH has been found in patients with inherited immunodeficiency disorders, including those due to mutations that are associated with HLH as well as others [27,44-46,121-124]. (See 'Immunodeficiency syndromes' above.)

Acquired immunodeficiencies have also been associated with HLH, including HIV/AIDS, hematopoietic cell transplantation, or kidney or liver transplant [100,125,126]. Sometimes HLH occurs in the setting of a concurrent infection or a lymphoproliferative syndrome [127-129]. In one small series, the development of HLH in kidney transplant patients appeared to be associated with the combination of splenectomy and the administration of anti-thymocyte globulin [130].

Features in adults — HLH presenting in adulthood is increasingly recognized [63,131-135]. Adults can have similar clinical features of HLH as children. As an example, a series of 775 adults with HLH reported similar predominance of fever (96 percent), splenomegaly (69 percent), and hepatomegaly (67 percent) [63].

However, emerging diagnostic criteria for adults with HLH indicate several differences from those used in pediatric patients. A Delphi analysis (a method for finding consensus using iterative anonymous questionnaires) from an expert panel determined the following clinical features to be important in adults [136]:

●Underlying predisposing disease

●Fever

●Organomegaly

●Cytopenias

●Elevated ferritin

●Elevated LDH

●Hemophagocytosis on the bone marrow aspirate

A 2015 review noted that HLH in adults is more likely to be associated with a hematologic malignancy, and an elevated ferritin level is less specific in adults due to the higher incidence of other inflammatory conditions [131].

The frequency of underlying conditions such as hematologic malignancies, infections, and rheumatologic conditions in adults with HLH have been illustrated in various case series:

●In a series of 162 adults with HLH, hematologic malignancies (especially non-Hodgkin lymphoma) were the most common trigger, seen in 92 (57 percent) [137]. An additional 40 patients (25 percent) had infections, which were caused by bacterial, viral, parasitic, or fungal organisms; six (4 percent) had both hematologic malignancy and infection. Additional analysis of this cohort identified a source of immunosuppression in 73 (45 percent) [138]. For 61, the source of immunosuppression was HIV infection; for the remainder, it was an immunosuppressive medication.

●Several single-institution studies focusing on HLH in adults have documented infection in 23 to 41 percent of patients and rheumatologic/autoimmune disease in 8 to 20 percent [139-141]. In a series of 30 patients who had testing for Epstein-Barr virus (EBV) DNA, 10 were found to be positive [142]. Adults with EBV-associated HLH have higher ferritin, LDH, AST, and ALT levels than those without EBV infection [143].

The reduced specificity of an extremely high ferritin in adults was illustrated in a series of 113 adults with a serum ferritin level >50,000 ng/mL (median age, 58) [150]. Of these, only 19 (17 percent) were ultimately diagnosed with HLH; 9 of the 17 had secondary HLH due to a malignancy and 6 of the 17 had secondary HLH due to infection. More common diagnoses than HLH included renal failure (65 percent), hepatocellular injury (54 percent), infection (46 percent), and hematologic malignancy (32 percent). Other diagnoses associated with extremely high ferritin levels in adults are discussed separately. (See 'Differential diagnosis' below and "Iron overload syndromes other than hereditary hemochromatosis", section on 'Extremely high ferritin levels'.)

The later age of onset in some adults may be explained by the presence of a mutation with partial residual protein function, which may be able to compensate in the setting of some immune triggers. (See 'Genetics' above.)

EVALUATION AND DIAGNOSTIC TESTING

Initial evaluation — Most patients with HLH are acutely ill with multiorgan involvement, cytopenias, liver function abnormalities, and neurologic symptoms. Patients may have already experienced a prolonged hospitalization or clinical deterioration without a clear diagnosis before the possibility of HLH is raised. A priority should be placed on rapid evaluation for organ involvement including testing for signs of bone marrow insufficiency, liver abnormalities, neurologic involvement, and immune activation, with the goal of starting treatment as rapidly as possible once the diagnosis (or a high likelihood) of HLH is established. The diagnostic approach is similar in infants, children, and adults [26].

The physical examination should focus on identifying rashes, bleeding, lymphadenopathy, hepatosplenomegaly, and neurologic abnormalities. A thorough examination for signs of other organ involvement (eg, cardiac, respiratory) is also necessary.

Many of the initial tests that are helpful in evaluating HLH will have already been done as part of the evaluation of an unexplained febrile illness that involves multiple organs. Others, including serum ferritin, triglycerides, and screening immunologic studies, should be done immediately.

Identifying signs of infection and specific organ injury is helpful in making the diagnosis of HLH, as well as for management of organ-specific complications. Based upon the symptoms and signs of specific organ involvement and/or the degree of suspicion for the presence of HLH, we perform the following studies in all patients:

●Cultures of blood, bone marrow, urine, cerebrospinal fluid, and other potentially infected body fluids; and viral titers and quantitative polymerase chain reaction testing for EBV, CMV, adenovirus, and other suspected viruses. It is critical to follow the levels of any identified virus during treatment with the appropriate anti-viral therapy.

●Abdominal ultrasound, if the physical examination for splenomegaly is inconclusive.

We do a rapid immunologic evaluation in those with a high clinical suspicion of HLH. (See 'Immunologic profile' below.)

Bone marrow evaluation — All patients should have examination of a bone marrow aspirate and biopsy to evaluate the cause of cytopenias and/or to detect hemophagocytosis. The bone marrow specimens should also be cultured and examined for infectious organisms and evidence of malignancy. Bone marrow cellularity can be high, low, or normal in HLH [26].

The reported incidence of hemophagocytosis on bone marrow examination ranges from 25 to 100 percent [137]. Some patients may only show hemophagocytosis later in the disease course, even as they are clinically improving [26]. A review of adult patients exhibiting hemophagocytosis in bone marrow aspirates revealed that 170 (64 percent) had lymphoma, especially T/NK and B cell lymphoma. Of 182 patients with sufficient clinical data to judge HLH-2004 diagnostic criteria for HLH, only 77 (29 percent) fulfilled 5 of 8 criteria (see 'Diagnostic criteria' below). Of those who had a malignancy, survival was a median of 9 months, versus 71.8 months in those with non-malignant disorders [151].

Infiltration of the bone marrow by activated macrophages is consistent with HLH. The macrophages in HLH do not have the cellular atypia associated with malignant histiocytes, and they are clearly a different cell from the CD1a-staining Langerhans cell of Langerhans cell histiocytosis (formerly called histiocytosis-X). It is helpful to stain the bone marrow for the hemoglobin-haptoglobin scavenger receptor CD163 to highlight the macrophages. This is often how many macrophages (hemophagocytosing and not) are seen in the bone marrow specimens of patients with HLH. (See 'Diagnosis' below.)

Specialized testing

Immunologic profile — Immunologic and cytokine studies are appropriate for those suspected of having HLH based on the results of the initial evaluation. (See 'Initial evaluation' above.)

We typically perform the following immunologic testing:

●Soluble IL-2 receptor alpha (sCD25 or sIL-2R)

●Tests of NK cell function/degranulation (eg, by flow cytometry for surface expression of the lysosomal-associated membrane protein 1 [LAMP-1, also called CD107alpha])

Findings consistent with HLH include elevated soluble IL-2 receptor alpha; reduced NK function or cell surface expression of CD107alpha; elevated sCD163; and reduced perforin, SAP, or XIAP. Peripheral blood T cell subsets show a normal helper/suppressor ratio, with low numbers of B cells and variable immunoglobulin levels [11,153-159]. Elevation of granzyme B has been found and is thought to be part of the immune signature of lymphocyte activation [160].

Of all the immunologic studies, we find soluble IL-2 receptor alpha (sIL-2R) to correlate most closely with disease activity [26]. The ratio of sIL-2R to serum ferritin may be useful in patients with lymphoma. A review of patients with lymphoma-associated HLH versus non-lymphoma-associated cases found that the former had a much higher ratio of sIL-2R to ferritin than the latter (ratio 8.56 versus 0.66) [161].

Levels of the soluble IL-2 receptor alpha will be available in one to two days, while the other tests take longer. Thus, therapy should not be delayed while awaiting results of this immunologic testing.

HLH associated with lymphoma can be challenging to differentiate from clinical presentations of sepsis. A study in 15 adults with lymphoma-associated HLH showed potential for the use of assays the cytokines CXCL9 and CXCL10; elevated levels had a high sensitivity and specificity for lymphoma-associated HLH compared to sepsis [162].

Genetic and HLA testing — Genetic testing (ie, identification of an HLH gene mutation) is indicated in all patients that meet the HLH diagnostic criteria, and those with a high likelihood of HLH based on the initial evaluation. For those with a known familial mutation or immunodeficiency syndrome, directed genetic analysis for the known mutation should be performed. For those without a known family mutation, one could base genetic testing on protein levels obtained during the initial evaluation:

Human leukocyte antigen (HLA) typing is indicated during the initial evaluation in preparation for identifying a donor for allogeneic hematopoietic cell transplantation. Performing this testing at the time of initial presentation avoids delays in identifying donors should they be needed. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

DIAGNOSIS — Ideally, the diagnosis of HLH is based upon fulfilling the published diagnostic criteria used in the HLH-2004 trial [26]. Not infrequently, however, a diagnosis of HLH is made in the patient who only partly meets the most stringent criteria because definitive HLH therapy must be initiated due to an inadequate response to general supportive care. A presumptive diagnosis depends upon a careful consideration of the presence or absence of the specific elements of the diagnostic criteria, the results of additional laboratory tests (eg, D-dimer and liver function tests), and a nuanced view of the overall clinical status.

Diagnostic criteria — We recommend that the diagnosis of HLH be based upon the following criteria, which were used in the HLH-2004 trial [26]:

It should be noted that these diagnostic criteria were devised for use in clinical trials and are therefore unlikely to capture every case of HLH. Because of the high mortality of HLH in the absence of appropriate treatment, we do not always require these diagnostic criteria to be met in order to initiate treatment. Specifically, we do not delay treatment while awaiting the results of genetic or specialized immunologic testing.

Diagnostic criteria are essentially the same in adults, with the caveat that adults are more likely to have a secondary form of HLH than children, and adults with secondary HLH are more likely to have an underlying malignancy as the cause.

It is common for a patient to only exhibit three or four of the eight diagnostic criteria, but also have CNS symptoms, hypotension, and renal or respiratory failure. To address this issue, a modification of the diagnostic criteria has been proposed [163]. In this approach, diagnosis requires three of four clinical findings (fever, splenomegaly, cytopenias, hepatitis) plus one of four immune markers (hemophagocytosis, increased ferritin, hypofibrinogenemia, absent or very decreased NK cell function) [163]. We also consider such criteria sufficient for diagnosis [26].

In contrast, we would not give HLH-specific therapy to a patient with fever, hepatitis, hypofibrinogenemia, and cytopenias, with a ferritin less than 3000 ng/mL and sCD25 only slightly above the age-related norm, because of the possibility that this could represent bacterial sepsis.

Other diagnostic considerations — Although hemophagocytosis and a very high serum ferritin are quite helpful in the diagnosis of HLH (see 'Serum ferritin levels' above), the following caveats are important to keep in mind:

●Hemophagocytosis is neither pathognomonic of, nor required for, the diagnosis of HLH. For patients with multiorgan failure and an immunologic profile typical of HLH who are acutely ill, serial bone marrow evaluations for hemophagocytosis can be conducted concurrently with initiation of treatment.

●Results from the HLH-94 study indicated that a ferritin level >500 ng/mL was only 80 percent specific for the diagnosis of HLH.

•Based on our experience, in children we generally view serum ferritin levels greater than 2000 to 3000 ng/mL in the proper clinical setting as concerning for HLH, and ferritin >10,000 ng/mL as highly suggestive of the disease. Support for our approach comes from a retrospective review of all patients admitted to Texas Children’s Hospital, Houston, TX with ferritin levels >500 mcg/L over a two-year period [76]. In this cohort, a ferritin level >500 mcg/L was 100 percent sensitive for HLH, but less specific. A ferritin level >10,000 mcg/L in children was 90 percent sensitive and 96 percent specific for HLH, with very minimal overlap with sepsis, infections, and liver failure. (See 'Serum ferritin levels' above.)

•In adults, we rely less heavily on an isolated serum ferritin elevation, as serum ferritin is less specific for HLH in adults. (See 'Features in adults' above.)

A scoring system has been developed to generate a diagnostic score referred to as an "Hscore" that estimates the probability of HLH [164]; this incorporates points for immunosuppression; fever; organomegaly; levels of triglycerides, ferritin, alanine aminotransferase, and fibrinogen; degree of cytopenias; and presence of hemophagocytosis on the bone marrow aspirate. An Hscore ≥250 confers a 99 percent probability of HLH, whereas a score of ≤90 confers a <1 percent probability of HLH.

DIFFERENTIAL DIAGNOSIS — HLH may simulate a number of common conditions that cause fever, pancytopenia, hepatic abnormalities, or neurologic findings. We find cytopenias, a very high ferritin level, and liver function abnormalities to be especially helpful in distinguishing HLH from these other conditions. The frequency of LFT abnormalities is so high in HLH that we believe the absence of LFT abnormalities should prompt a thorough search for an alternative diagnosis. (See 'Cytopenias' above and 'Serum ferritin levels' above and 'Liver function and coagulation abnormalities' above.)

It is also important to remember that HLH can develop in association with many of the conditions in its differential diagnosis.

●Macrophage activation syndrome (MAS) – MAS should be thought of as a form of HLH associated with a rheumatologic disease, rather than as a separate clinical entity. (See 'Rheumatologic disorders/MAS' above.)

●Infection/sepsis – Systemic infections and/or sepsis share many features with HLH, including fever, cytopenias, and hepatic involvement. Both sepsis and HLH can have findings of disseminated intravascular coagulation and widespread inflammation with cytokine abnormalities. Unlike HLH, which is often triggered by a viral infection, sepsis is typically caused by a bacterial or fungal microorganism, and sepsis is typically not characterized by ongoing lymphocyte activation. While there is no ideal test to distinguish between sepsis and HLH, an extremely high ferritin and elevated lactate dehydrogenase level were highly predictive of a subsequent diagnosis of HLH in a series of 19 children with an initial diagnosis of fever of unknown origin [75]. Ferritin levels tend to be static in patients with infections, but are prone to dramatic increases in those with HLH. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

●Liver disease/liver failure – Primary liver disease and HLH can both present with hepatomegaly and elevated liver function tests. Both can cause a coagulopathy with prolonged PT and aPTT, low fibrinogen, and elevated D-dimer and both can cause encephalopathy. Unlike liver disease, HLH is a multisystem disorder. Those with HLH typically have more extensive organ involvement, cytopenias, extremely high ferritin, and neurologic findings. Cytokine profiles seen in HLH are not typically seen in primary liver disease. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis".)

●Encephalitis – Encephalitis can result from infection, autoimmunity, and a number of viral infections; and the clinical manifestations can range from subtle neurologic deficits to complete unresponsiveness. The neurologic presentation of those with encephalitis can thus be identical to those with HLH. However, those with HLH typically have more extensive organ involvement, cytopenias, liver abnormalities, and high ferritin, whereas findings in encephalitis are typically confined to the central nervous system. (See "Acute viral encephalitis in children: Clinical manifestations and diagnosis" and "Viral encephalitis in adults".)

●Autoimmune lymphoproliferative syndrome (ALPS) – ALPS is an immune dysregulation syndrome caused by genetic defects in the machinery for FAS-mediated apoptosis, which leads to expansion of some autoreactive lymphocyte populations. Patients present with hepatosplenomegaly, rash, and autoimmune cytopenias, along with other autoimmune manifestations that could mimic findings of HLH (eg, autoimmune hepatitis, Guillain Barré syndrome). Unlike those with HLH, patients with ALPS typically do not manifest multiorgan failure and signs of excessive inflammation such as extremely high ferritin levels and severe liver failure. (See "Autoimmune lymphoproliferative syndrome (ALPS): Clinical features and diagnosis".)

●Drug reaction with eosinophilia and systemic symptoms (DRESS) – DRESS is a severe drug-induced hypersensitivity reaction possibly initiated by viral reactivation. Like HLH, DRESS is characterized by fever and liver function test abnormalities. DRESS can also be associated with hemophagocytosis, although this is rare [166]. Unlike HLH, DRESS is characterized by temporal relationship to a drug, eosinophilia and skin rash. DRESS is unlikely to cause an extremely high ferritin or cytopenias, which are found in most patients with HLH. (See "Drug eruptions", section on 'Drug reaction with eosinophilia and systemic symptoms (DRESS)'.)

●Child abuse – Child abuse and HLH may present with similar features involving the central nervous system [167,168]. The majority of child abuse victims with brain injury also have some laboratory abnormalities such as a prolonged aPTT [169]. However, cytopenias, abnormal liver function tests, and high serum ferritin typical of HLH are not features of child abuse. (See "Differential diagnosis of suspected child physical abuse".)

●Kawasaki disease – Kawasaki disease, a vasculitis that predominantly affects children, is characterized by signs of widespread inflammation that include fever, rash, and lymphadenopathy as well as elevated triglycerides and abnormal cerebrospinal fluid findings. Kawasaki disease typically causes bilateral conjunctivitis and mucositis, as well as cardiac findings (eg, coronary artery aneurysms), findings that are much less common in HLH. Additional features that help distinguish Kawasaki disease from HLH include the more likely presence of cytopenias and liver abnormalities with HLH. A patient with the diagnosis of Kawasaki disease, especially if "atypical", whose symptoms do not respond to intravenous immune globulin (IVIG) therapy, should be evaluated for HLH. Kawasaki disease can act as a trigger for HLH, so its diagnosis does not eliminate the possibility of HLH. (See "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease: Complications", section on 'Cardiac complications'.)

●Thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or drug-induced thrombotic microangiopathy (DITMA) – TTP, HUS, and DITMA (also called drug-induced TTP) are characterized by endothelial damage, microvascular thrombosis, and anemia; fever, neurologic findings, or renal failure may be present. Unlike the anemia of HLH, the anemia in these syndromes is microangiopathic (ie, Coombs negative, characterized by schistocytes). Patients with TTP, HUS, or DITMA generally do not have rising ferritin or liver function abnormalities, although a DITMA syndrome associated with quinine may have multiorgan failure. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Drug-induced thrombotic microangiopathy".)

●Transfusion-associated graft-versus-host disease (ta-GVHD) – Ta-GVHD is a rare complication of transfusion of any non-irradiated blood component. It occurs when viable donor lymphocytes in the transfusion attack the recipient's tissues (skin, bone marrow, gastrointestinal tract), often fatally. It is most common after hematopoietic cell transplantation but can also occur in immunocompetent individuals who have a partial human leukocyte antigen (HLA) match with the donor (eg, in ethnically homogenous populations or after directed donation). The typical presentation includes fever, rash, pancytopenia, and elevated liver enzymes, 4 to 30 days after transfusion. High ferritin levels and hemophagocytosis in the bone marrow can also be seen. Unlike HLH, skin biopsy in ta-GVHD shows vacuolization of the basal layer and a histiocytic infiltrate, and sometimes the pathognomonic finding of satellite dyskeratosis. In cases where the two diagnoses cannot be distinguished, a trial of dexamethasone, and, if not sufficient, etoposide, can be used. (See "Transfusion-associated graft-versus-host disease".)

SUMMARY

●Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. It is most common in infants and young children but can affect patients of any age, with or without a predisposing familial condition. (See 'Introduction' above and 'Epidemiology' above.)

●Patients may have already experienced a prolonged hospitalization or clinical deterioration without a clear diagnosis before the possibility of HLH is raised. A priority should be placed on rapid evaluation, with the goal of starting treatment as soon as possible. (See 'Initial evaluation' above.)

●Many patients with HLH have a predisposing genetic defect, and/or an immunologic trigger, which can include infection, malignancy, rheumatologic disorder such as juvenile idiopathic arthritis, or another disorder associated with immune dysregulation. These genetic defects and immunologic triggers should be identified in all patients. (See 'Genetics' above and 'Associated illnesses' above.)

●The initial evaluation includes a complete blood count with differential, coagulation studies, serum ferritin, liver function tests, triglycerides, blood cultures, and viral testing. The bone marrow should be examined for the cause of cytopenias, infectious organisms, hemophagocytosis, and macrophage infiltration; and sent for cultures. All patients should have cerebrospinal fluid analysis and magnetic resonance imaging of the brain. Computed tomography scans of the neck, chest, abdomen and pelvis should be done to evaluate for possible malignancy. (See 'Initial evaluation' above and 'Bone marrow evaluation' above.)

●For those with a high clinical suspicion, specialized testing of immunologic parameters and genetic testing are also indicated. HLA typing is done in preparation for possible allogeneic hematopoietic cell transplantation. (See 'Specialized testing' above.)

●The diagnosis of HLH is made by identifying a mutation in an HLH gene, or by fulfilling five of eight diagnostic criteria. Many patients fit only three or four of the eight criteria, yet have clinical evidence of HLH and require HLH-specific treatment. Modified diagnostic criteria may also be used. Hemophagocytosis, while often seen, is neither necessary nor sufficient for the diagnosis of HLH. (See 'Diagnosis' above.)

●The differential diagnosis of HLH includes several multisystem illnesses characterized by fever, hepatic failure, and neurologic symptoms. Many of the conditions in the differential diagnosis of HLH can also cause HLH. We consider macrophage activation syndrome to be a form of HLH associated with a rheumatologic condition rather than a distinct entity. (See 'Differential diagnosis' above and 'Rheumatologic disorders/MAS' above.)